SMALL MOLECULE ANALOGS OF E4orf1

ABSTRACT

The invention relates to amino nitrile compounds. Such compounds can increase glucose uptake by cells and preferably do not substantially increase adipogenesis.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.61/983,142, filed Apr. 23, 2014 the entire disclosure of which is herebyincorporated by reference herein.

BACKGROUND OF THE INVENTION

The world is in the middle of an obesity epidemic, which appears to befollowed by an epidemic of type 2 diabetes. Although lifestylemodification to induce weight loss is a cornerstone of preventing andtreating diabetes, inducing a substantial and sustained weight loss hasremained highly challenging. Therefore, additional drugs are required toeffectively manage diabetes and its complications. However, the drugtreatment of diabetes offers additional challenges. Diabetes is oftenassociated with impaired insulin signaling, leading to a reduction inglucose uptake by adipose tissue and skeletal muscle and an increase inrelease of glucose in circulation, collectively contributing to theraised blood glucose levels encountered in diabetes. Moreover, diabetesis associated with increased deposition of fat in the liver, which mayfurther impair hepatic function. Considering these challenges, a drugthat can increase glucose uptake by adipose tissue and skeletal muscle,reduce hepatic glucose output and fat accumulation, even in presence ofimpaired insulin signaling and obesity, would be highly desirable foreffective management of diabetes. Proteins of Ad36, a human adenovirusappear to offer a great template to design such a drug, as describedbelow.

Briefly, in animal models, experimental infection with Ad36significantly increases adiposity, but improves glycemic control andattenuates lipid accumulation in the liver, despite high fat diet(Dhurandhar N. V., et al., Obes Rev., 14(9):721-35 (2013); KrishnapuramR., et al., Am J Physiol Endocrinol Metab., 300(5):E779-89 (2011);Dhurandhar N. V., Lancet Infect Dis., 11(12):963-69 (2011); Pasarica M.,et al., Obesity (Silver Spring), 14(11):1905-13 (2006)). Humans, who arenaturally exposed to Ad36 infection show cross-sectional and temporalassociations with obesity and better glycemic control and lower hepaticlipid levels (Krishnapuram R., et al., Am J Physiol Endocrinol Metab.,300(5):E779-89 (2011); Lin W., et al., Diabetes Care, 36(3):701-07(2013); Yamada T., et al., PLoS ONE, 7(7):E42031 (2012); Shang Q., etal., Obesity (Silver Spring), 22(3):895-00 (2014); Trovato G. M., etal., Int J Obes. (Lond), 33(12):1402-09 (2009); Trovato G. M., et al.,Liver Int., 30(2):184-90 (2010); Trovato G. M., et al., Dig Dis Sci.,57(2):535-44 (2012)). Cell culture studies indicate that the E4orf1protein of Ad36 is necessary and sufficient for the effects of Ad36 onadiposity, glucose disposal and hepatic lipid content (Rogers P. M., etal., Int J Obes. (Lond), 32(3):397-06 (2008); Dhurandhar E. J., et al.,PLoS ONE, 6(8): E23394 (2011); Dhurandhar E. J., et al., PLoS ONE,7(10):E47813 (2012)). Working independent of the proximal insulinsignaling (Krishnapuram R., et al., Int J Obes., 37(1):146-53 (2013)),Ad36 E4orf1 increases uptake of glucose by preadipocytes, adipocytes,and myoblasts, and it reduces glucose release from hepatocytes (RogersP. M., et al., Int J Obes. (Lond), 32(3):397-06 (2008); Dhurandhar E.J., et al., PLoS ONE, 6(8):E23394 (2011); Dhurandhar E. J., et al., PLoSONE, 7(10):E47813 (2012)). Moreover, Ad36 E4orf1 promotes lipid export,reduces lipid uptake, and promotes lipid oxidation in hepatocytes(Dhurandhar E. J., et al., PLoS ONE, 7(10):E47813 (2012)), which maycollectively reduce hepatic lipid storage. Recent data show that E4orf1can improve hyperglycemia in high fat fed mice (Ha-Na N., et al.,Obesity Week, 2013, S211). Importantly, this action of E4orf1 appears tobe independent of proximal insulin signaling, high fat diet, or weightloss.

As the epidemic of obesity continues unabated, infectobesity, obesity ofinfectious origin, has been receiving increasing attention in the recentyears (Rossner S., Lakartidningen, 102(24-25):1896-8 (2005); Astrup A.,et al., Int J Obes Relat Metab Disord., 22(4):375-6 (1998); Powledge T.M., Lancet Infect Dis., 4(10):599 (2004)). Although many factorscontribute to the etiology of obesity, a subset of obesity may be causedby infections. In the last two decades, 10 obesity-promoting pathogenshave been reported (Dhurandhar N. V., et al., Genetics and Hormones,20(3): 33-39 (2004)). The first human virus, adenovirus type 36 (Ad-36),was reported that caused obesity in experimentally infected animals(Dhurandhar N. V., et al., Int J Obesity, 24:989-96 (2000); DhurandharN. V., et al., Int J Obesity, 25:990-96 (2001); Dhurandhar N. V., etal., J Nutrition, 132:3155-60 (2002)) and showed association with humanobesity (Atkinson R. L., et al., Int J Obesity, 29:281-86 (2005)).In-vitro experiments have shown that Ad-36 infection of ratpreadipocytes (3T3-L1) and human preadipocytes promote theirproliferation and differentiation (Vangipuram S. D., et al., ObesityResearch, 12:770-77 (2004)).

Ad-36 stimulates preadipocytes (pre-fat cells) to differentiate intoadipocytes (fat cells), and increases the number of fat cells and theirlipid content (Id.). Ad-36 can induce differentiation of preadipocyteseven in absence of conventional differentiation inducers such as thecocktail of methyl isobutyl xanthine, dexamethasone, and insulin (MDI).A similar effect of the virus is observed in human adipose derived stemcells (Id.). Rats infected with Ad-36 showed greater adiposity butparadoxically lower insulin resistance 7 months post-infection (PasaricaM., et al., Obesity Research, 12 (supplement):A122 (2004)). Moreover,fat cells from uninfected rats when infected with Ad-36 show increasedglucose uptake, indicating greater insulin sensitivity (Dhurandhar N.V., et al., Obesity Research, 11:A38 (2003)).

Factors required for increased insulin sensitivity include greaterpreadipocyte number and differentiation, and activation of cAMP andinsulin signaling pathway enzymes (e.g., phosphotidyl inositol-3 kinase(PI3K or PI3 kinase)). Preadiopcyte differentiation in turn is modulatedby activation of PI3 kinase and cAMP signaling pathways (Hansen J. B.,et al., J Biol Chem., 276(5):3175-82 (2001); Reusch J. E., et al., MolCell Biol., 20(3):1008-20 (2000); Chiou G. Y., et al., J Cell Biochem.,94(3):627-34 (2005); Cornelius P., et al., J Cell Physiol.,146(2):298-08 (1991); Burgering B. M., et al., Nature, 376(6541):599-02(1995); Magun R., et al., Endocrinology, 137(8):3590-3 (1996)). Ad-36has been shown to increase preadipocyte replication, the number ofdifferentiated adipocytes, and PI3 kinase pathway (Pasarica M., et al.,FASEB J, 19(4):A70 (2005)).

The liver has a predominate role in fat metabolism and normallyaccumulates lipids (fat), but only to “normal levels.” Excessive lipidaccumulation in hepatocytes results in hepatic steatosis, which ismetabolically harmful and can result from a variety of liverdysfunctions, such as decreased beta-oxidation or decreased secretion oflipoproteins. Another of the many functions of the liver is to releaseglucose into circulation. In healthy individuals, liver cells releaseglucose regularly to regulate blood glucose levels. In contrast, inindividuals with diabetes, liver cells release glucose uncontrollably,which increase blood glucose levels. Therefore, reducing glucose releasefrom liver cells (hepatocytes) can be very effective in controllingdiabetes.

Excessive lipid accumulation in the liver may contribute to insulinresistance, a condition in which insulin has decreased effectivenesslowering blood sugar, and thus poor glycemic control. Adiponectin, aprotein secreted by fat tissue (adipose tissue) improves insulinsensitivity in many ways. Adiponectin acts via adiponectin receptorsAdipoR1 and AdipoR2 in the liver to activate AMPK and PPARaC pathways(Heiker, J. T., et al., Biol. Chem., 391:1005-18 (2010)), to decreasesystemic and hepatic insulin resistance, and to attenuate liverinflammation and fibrosis (Heiker et al.). It is a strong determinant ofhepatic lipid content, as indicated by mice models of adiponectin“knock-out” or overexpression (Nawrocki, A. R., et al., J. Biol. Chem.,281:2654-60 (2006); Kim, J. Y., et al., J. Clin. Invest., 117:2621-37(2007)). Adiponectin is thought to lower hepatic steatosis by theup-regulation of AMPK-mediated hepatic lipid oxidation (Xu, A., et al.,J. Clin. Invest., 112:91-00 (2003)).

Non-alcoholic fatty liver disease (NAFLD) affects up to 20% of adults inthe U.S., and includes the excessive accumulation of fat in the liver(hepatic steatosis). It is often associated with obesity and insulinresistance (Fabbrini, E. et al., Proc. Natl. Acad. Sci., USA106:15430-35 (2009); Deivanayagam, S. et al., Am. J. Clin. Nutr.,88:257-62 (2008)). The prevalence of NAFLD is about 70-80% in adultswith type 2 diabetes or obesity (Targher, G., et al., Diabetes Care,30:1212-18 (2007); Bellentani, S., et al., Dig. Dis., 28:155-61 (2010);Parekh, S. et al., Gastroenterology, 132:2191-07 (2007)), 3-10%, in allchildren, and up to 40-70% in obese children (Bellentani et al.). NAFLDis associated with greater overall and liver-related mortality (Adams,L. A., et al., Gastroenterology, 129:113-21 (2005); Ekstedt, M., et al.,Hepatology, 44:865-73 (2006)). In addition to steatosis, inflammationand fibrosis can develop and NAFLD may progress to non-alcoholicsteato-hepatitis (NASH), cirrhosis, liver failure and hepatocellularcarcinoma. While steatosis is potentially reversible, once it progressesto NASH, there are no established treatments, and the few availablemedications show limited success (Gupta A. K., et al., J DiabetesComplications, 2009; Sanyal A. J., et al., N Engl J Med., 362:1675-85(2010)). Therefore, the timely prevention and/or treatment of hepaticsteatosis is critical. However, even for NAFLD, drug treatment hasmarginal success (Duvnjak M., et al., J Physiol Pharmacol., 60 Suppl7:57-66 (2009)), and reducing dietary fat intake and obesity are themainstay of treatment (Mishra P., et al., Curr Drug Discov Technol.,4:133-140 (2007)). Despite the obvious health benefits, compliance withlifestyle changes to achieve sustained improvements in diet or obesityhas proved challenging for the general population.

While excess adiposity or a high fat (HF)-diets are risk factors forNAFLD, Adenovirus 36 (Ad36) attenuates hepatic steatosis in mice despitea continued HF-diet and without a reduction in visceral or subcutaneousadiposity. Ad36 appears to qualitatively alter the metabolic quality ofadipose tissue to attenuate HF-diet induced hepatic steatosis. Thischange in the metabolic quality of adipose tissue by Ad36 includesgreater uptake and reduced release of fatty acids and greateradiponectin secretion (Rogers, P. M., et al., Diabetes, 57:2321-31(2008); Pasarica M., et al., Stem Cells, 26:969-78 (2008)). Thethiazolidinedione (TZDs) class of drugs can also improve metabolicquality of adipose tissue, up-regulate adiponectin, and improve hepaticsteatosis (Nawrocki, A. R., et al., J Biol Chem., 281:2654-60 (2006);Lutchman G., et al., Clin Gastroenterol Hepatol., 4:1048-52 (2006);Shen, Z., et al., Am J Physiol Gastrointest Liver Physiol., 298:G364-74(2010)). However, serious side effects of TZDs have been reported(Habib, Z. A., et al., J Clin Endocrinol Metab., 95:592-00 (2010);Ramos-Nino, M. E., et al., BMC Med., 5:17 (2007); Lipscombe, L. L. etal., JAMA, 298; 2634-43 (2007)).

Ad36 does not cause morbidity or unintended mortality in animals. Inaddition, Ad36 appears to have distinct advantages over the action ofthe TZDs, particularly in the presence of a HF-diet. Unlike the TZDs,Ad36 does not increase adiposity in HF-fed mice (Fernandes-Santos, C.,et al., Pancreas, 38:E80-86 (2009); Fernandes-Santos, C., et al.,Nutrition, 25:818-27 (2009)). In the presence of a HF-diet, TZDs canimprove glycemic control, but they concurrently promote lipid storage invarious organs, including the liver (Fernandes-Santos, C., et al.,Pancreas, 38:E80-86 (2009); Todd, M. K., et al., Am J Physiol EndocrinolMetab., 292:E485-93 (2007); Kuda, O., et al., J Physiol Pharmacol.,60:135-140 (2009)). This and other side effects limit the clinicalutility of TZDs.

Harnessing certain properties of viruses for beneficial purposes hasbeen creatively used for several years, including the use ofbactericidal properties of a bacteriophage virus (Hanlon, G. W., Int JAntimicrob Agents, 30:118-28 (2007)), the oncolytic ability of a mutantadenovirus (Bischoff, J. R., et al., Science, 274:373-76 (1996)), or theuse of Herpes simplex virus and several other viruses for the treatmentof cancers (Crompton, A. M., et al., Curr Cancer Drug Targets, 7:133-39(2007)), alone, or with various synergistic drugs (Pan, Q., et al., MolCell Biochem., 304 (1-2):315-23 (2007); Libertini, S., et al.,Endocrinology, 148(11):5186-94 (2007).

Therefore, a need exists for agents that improve glucose uptake andpreferably do not increase adiposity.

SUMMARY OF THE INVENTION

In some aspects, embodiments disclosed herein relate to compounds andpharmaceutical compositions comprising structures of general Formula I,pharmaceutically acceptable salts thereof, and/or solvates thereof:

wherein Ar₁ is selected from the group consisting of 6-membered aryl and6-membered heteroaryl, each of which is optionally substituted, Ar₂ isselected from the group consisting of 6-membered aryl and 6-memberedheteroaryl, each of which is optionally substituted.

In some aspects, embodiments disclosed herein relate to compounds andpharmaceutical compositions comprising structures of general Formula II,pharmaceutically acceptable salts thereof, and/or solvates thereof:

wherein

Z¹, Z², Z³, Z⁴, Z⁵ and Z⁶ are each independently selected from the groupconsisting of

null, alkyl, aryl, heteroaryl, alkoxy, hydroxy, thiol, trifluoromethyl,nitrile, isonitrile and halogen, wherein the alkyl, aryl, heteroaryl,alkoxy, hydroxy and thiol may be optionally substituted, with theproviso that no more than one of Z¹, Z² and Z³ is

and no more than one of Z⁴, Z⁵ and Z⁶ is

It will be appreciated by those skilled in the art that any carbon atomin Ar₁ and Ar₂ that is not bonded to Z¹, Z², Z⁴, Z⁵ or Z⁶ will be bondedto hydrogen;

R¹ and R² are independently selected from the group consisting ofhydroxy, alkoxy, and halo, and R³ is selected from the group consistingof null, hydroxy, alkoxy, and halo, or R¹ and R² taken together with theboron atom to which they are bonded form a cyclic boronate ester and R³is null. When four bonds to boron are present (i.e., R³ is not null),boron bears a formal negative charge and the structure further comprisesa counter cation, such as potassium, sodium, mercury, or lithium; and

X¹, X², X³, X⁴ and X¹ are independently selected from the groupconsisting of O, C, S, B—R⁴ and N, with the proviso that no more thantwo of X¹, X², X³, X⁴ and X⁵ are O, S, B(—R⁴) or N; and each R⁴ isindependently selected from the group consisting of hydrogen, optionallysubstituted hydroxy, optionally substituted alkoxy and optionallysubstituted alkyl.

In certain aspects of compounds of Formula II, one or two of X¹, X², X³,X⁴ and X⁵ are N, and preferably the others are C. For example, in someaspects, X² is N and X¹, X³, X⁴ and X⁵ are each C. Certain compounds ofthis aspect are substituted on Ar₁ and at least one of Z¹, Z² and Z³ isnot null. In certain compounds of this aspect, Ar₂ is substituted.

In more particular examples, Z⁴ is not null and Z⁵, Z⁶ are null. In suchcompounds, Z⁴ can be

R¹, R², and R³ are as defined in Formula II. Such compounds are ofFormula III:

wherein X¹, X², X³, X⁴ and X⁵; Z¹, Z², Z³ and Z⁴ are as defined inFormula II. In preferred embodiments, Z⁴ is para to the carbon atom thatis bonded to the amino nitrile moiety.

In some aspects, embodiments disclosed herein relate to methods to treatdiseases selected from the group consisting of hyperglycemia, insulinresistance, prediabetes, diabetes (e.g., diabetes type 1, diabetes type2), Alzheimer's disease, hepatic steatosis, NAFLD, non-alcoholicsteato-hepatitis (NASH), liver dysfunction (e.g., liver dysfunctioncharacterized by fatty liver and/or insulin resistance) and combinationsthereof, comprising administering to a subject in need thereof atherapeutically effective amount of a compound of Formula I or FormulaII or Formula III, pharmaceutically acceptable salts thereof, and/orsolvates thereof, optionally with a pharmaceutically acceptable vehicle.

In some aspects, embodiments disclosed herein relate to methods to treatdiseases selected from the group consisting of hyperglycemia, insulinresistance, prediabetes, diabetes type 1, diabetes type 2, Alzheimer'sdisease, hepatic steatosis, NAFLD, non-alcoholic steato-hepatitis(NASH), liver dysfunction (e.g., liver dysfunction characterized byfatty liver and/or insulin resistance) and combinations thereof,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of Formula I or II or III,pharmaceutically acceptable salts thereof, and/or solvates thereof,optionally with a pharmaceutically acceptable vehicle.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure is directed, in part, to compounds that improveglucose uptake, and preferably do not substantially increase adiposity(e.g., less than 5% increase in adiposity), pharmaceutical compositionscomprising the compounds and methods of treating diseases disclosedherein by administering the compounds or pharmaceutical compositions.

Ad36 improves glycemic control and has been shown to reduce liver fat inanimals. Despite these benefits, it is impractical to use Ad36 infectionto improve diabetes in humans. The E4orf1 protein of Ad36 adenovirus hasbeen indicated to be necessary and sufficient for Ad36-induced increasedcellular glucose uptake. Ad-36 E4orf1 protein has been shown to increaseinsulin sensitivity and promote preadipocyte differentiation. Thisprotein can be used to increase insulin sensitivity and amelioratediabetes. E4orf1 is not a secreted protein, thus it needs to bedelivered to cells via a delivery system. (See WO2007/064836 andWO2012/006512, incorporated herein, in their entirety). As disclosedherein, chemical analogs that are able to mimic desirable activities ofE4orf1 have been developed, and can be used to increase insulinsensitivity and ameliorate diabetes.

In accordance with embodiments disclosed herein, E4orf1 was utilized asa template to design compounds of Formulas I, II and III. The approachemployed was to develop small molecules that mimic the action of E4orf1protein. Compounds of Formulas I, II and III were designed as smallmolecule surrogates of E4orf1 protein based on the cellular action ofE4orf1, its molecular partners, and various cell signaling pathwaysinvolved in the action of E4orf1.

In one aspect, the compound is of general Formula I, pharmaceuticallyacceptable salts thereof, and/or solvates thereof:

wherein Ar₁ is selected from the group consisting of 6-membered aryl and6-membered heteroaryl, each of which is optionally substituted, Ar₂ isselected from the group consisting of 6-membered aryl and 6-memberedheteroaryl, each of which is optionally substituted.

In other aspects, the compound is of general Formula II,pharmaceutically acceptable salts thereof, and/or solvates thereof:

wherein

-   -   Z¹, Z², Z³, Z⁴, Z⁵ and Z⁶ are each independently selected from        the group consisting of

null, alkyl, aryl, heteroaryl, alkoxy, hydroxy, thiol, trifluoromethyl,nitrile, isonitrile and halogen, wherein the alkyl, aryl, heteroaryl,alkoxy, hydroxy and thiol may be optionally substituted, with theproviso that no more than one of Z¹, Z² and Z³ is

and no more than one of Z⁴, Z⁵ and Z⁶ is

It will be appreciated by those skilled in the art that any carbon atomin Ar₁ and Ar₂ that is not bonded to Z¹, Z², Z³, Z⁴, Z⁵ or Z⁶ will bebonded to hydrogen;

R¹ and R² are independently selected from the group consisting ofhydroxy, alkoxy, and halo, and R³ is selected from the group consistingof null, hydroxy, alkoxy, and halo, or R¹ and R² taken together with theboron atom to which they are bonded form a cyclic boronate ester and R³is null. When four bonds to boron are present (i.e., R³ is not null),boron bears a formal negative charge and the structure further comprisesa counter cation, such as potassium, sodium, mercury, or lithium; and

X¹, X², X³, X⁴ and X⁵ are independently selected from the groupconsisting of O, C, S, B—R⁴ and N, with the proviso that no more thantwo of X¹, X², X³, X⁴ and X⁵ are O, S, B(—R⁴), N; and each R⁴ isindependently selected from the group consisting of hydrogen, optionallysubstituted hydroxy, optionally substituted alkoxy and optionallysubstituted alkyl.

In certain aspects of compounds of Formula II, one or two of X¹, X², X³,X⁴ and X⁵ are N, and preferably the others are C. For example, in someaspects, X² is N and X¹, X³, X⁴ and X⁵ are each C. Certain compounds ofthis aspect are substituted on Ar₁ and at least one of Z¹, Z² and Z³ isnot null. In certain compounds of this aspect, Ar₂ is substituted. Inmore particular examples, Z⁴ is not null and Z⁵, Z⁶ are null. In suchcompounds, Z⁴ can be

R¹, R², and R³ are as defined in Formula II. Such compounds are ofFormula III.

In some aspects, embodiments disclosed herein relate to compounds andpharmaceutical compositions comprising structures of general FormulaIII, pharmaceutically acceptable salts thereof, and/or solvates thereof:

wherein X¹, X², X³, X⁴ and X⁵; Z¹, Z², Z³ and Z⁴ are as defined inFormula II. In preferred embodiments, Z⁴ is para to the carbon atom thatis bonded to the amino nitrile moiety.

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean that range which wouldencompass the recited value and the range which would be included byrounding up or down to that figure as well, taking into accountsignificant figures.

Although the chemical terms used herein are intended to have theirordinary meaning as recognized by those skilled in the art, thefollowing terms are provided for guidance.

The term “alkyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl group containing from 1 to 20carbon atoms. In certain embodiments, the alkyl group may comprise from1 to 10 carbon atoms. In further embodiments, the alkyl group maycomprise from 1 to 6 carbon atoms. Alkyl groups may be optionallysubstituted as defined herein. Examples of alkyl groups include methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,pentyl, iso-amyl, hexyl, octyl, noyl and the like. The term “alkylene,”as used herein, alone or in combination, refers to a saturated aliphaticgroup derived from a straight or branched chain saturated hydrocarbonattached at two or more positions, such as methylene (—CH₂—). Unlessotherwise specified, the term “alkyl” may include “alkylene” groups.

The term “aryl,” as used herein, alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch polycyclic ring systems are fused together. The term “aryl”embraces aromatic groups such as phenyl, naphthyl, anthracenyl, andphenanthryl.

The term “halo,” or “halogen,” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “heteroaryl,” as used herein, alone or in combination, refersto a 3 to 7 membered unsaturated heteromonocyclic ring, or a fusedmonocyclic, bicyclic, or tricyclic ring system in which at least one ofthe fused rings is aromatic, which contains at least one atom selectedfrom the group consisting of O, S, and N. In certain embodiments, theheteroaryl may comprise from 5 to 7 carbon atoms. The term also embracesfused polycyclic groups wherein heterocyclic rings are fused with arylrings, wherein heteroaryl rings are fused with other heteroaryl rings,wherein heteroaryl rings are fused with heterocycloalkyl rings, orwherein heteroaryl rings are fused with cycloalkyl rings. Examples ofheteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl,pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl,thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl,isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl,benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl,benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl,benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl,tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl and the like. Exemplary tricyclicheterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl,dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like. Inparticular embodiments, a heteroaryl group may be limited to possessingtwo heteroatoms total wherein the heteroatoms are selected from O and N.

The term “lower,” as used herein, alone or in a combination, where nototherwise specifically defined, means containing from 1 to and including6 carbon atoms.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkylamido wouldrepresent an alkyl group attached to the parent molecule through anamido group, and the term alkoxyalkyl would represent an alkoxy groupattached to the parent molecule through an alkyl group.

When a group is defined to be “null,” what is meant is that the group isabsent.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently selected from the following groups or aparticular designated set of groups, alone or in combination: loweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lowerhaloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl,phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, loweracyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester,lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, loweralkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lowerhaloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonicacid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃, CO₂CH₃, CO₂H,pyridinyl, thiophene, furanyl, lower carbamate, halophenyl,hydroxyphenyl, haloalkyl, hydroxyalkyl, and lower urea. Two substituentsmay be joined together to form a fused five-, six-, or seven-memberedcarbocyclic or heterocyclic ring consisting of zero to threeheteroatoms, for example forming methylenedioxy or ethylenedioxy. Anoptionally substituted group may be unsubstituted (e.g., —CH₂CH₃), fullysubstituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) orsubstituted at a level anywhere in-between fully substituted andmonosubstituted (e.g., —CH₂CF₃). Where substituents are recited withoutqualification as to substitution, both substituted and unsubstitutedforms are encompassed. Where a substituent is qualified as“substituted,” the substituted form is specifically intended.Additionally, different sets of optional substituents to a particularmoiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.”

Asymmetric centers exist in the compounds disclosed herein. For example,in Formulas I, II and III, the aminonitrile center comprises astereogenic carbon, i.e. a carbon bearing four different substituents.These centers may be designated by the symbols “R” or “S,” depending onthe configuration of substituents around the chiral carbon atom. Itshould be understood that the invention encompasses all stereochemicalisomeric forms, including diastereomeric, enantiomeric, and epimericforms, as well as d-isomers and 1-isomers, and mixtures thereof.Individual stereoisomers of compounds can be prepared synthetically fromcommercially available starting materials which contain chiral centersor by preparation of mixtures of enantiomeric products followed byseparation such as conversion to a mixture of diastereomers followed byseparation or recrystallization, chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method known in the art. Starting compounds ofparticular stereochemistry are either commercially available or can bemade and resolved by techniques known in the art. Additionally,compounds may exist as tautomers; all tautomeric isomers are provided bythis invention. Additionally, the compounds disclosed herein can existin unsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms.

The term “disease” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder” and“condition” (as in medical condition), in that all reflect an abnormalcondition of a subject, the subject being, for example, a human oranimal body or of one of its parts that impairs normal functioning, istypically manifested by distinguishing signs and symptoms, and causesthe human or animal to have a reduced duration or quality of life.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a therapeutic condition or disorderdescribed in the present disclosure. Such administration encompassesco-administration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofactive ingredients or in multiple, separate capsules for each activeingredient. In addition, such administration also encompasses use ofeach type of therapeutic agent in a sequential manner. In either case,the treatment regimen will provide beneficial effects of the drugcombination in treating the conditions or disorders described herein.

The term “inhibition” (and by extension, “inhibitor”) as used hereinencompasses all forms of functional protein (enzyme, kinase, receptor,channel, etc., for example) inhibition, including neutral antagonism,inverse agonism, competitive inhibition, and non-competitive inhibition(such as allosteric inhibition). Inhibition may be phrased in terms ofan IC₅₀, defined below.

The term “therapeutically acceptable” refers to those compounds (orsalts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitablefor use in contact with the tissues of patients without undue toxicity,irritation, and allergic response, are commensurate with a reasonablebenefit/risk ratio, and are effective for their intended use.

As used herein, reference to “treatment” of a subject is intended toinclude prophylaxis.

The term “subject” means all mammals including humans. Examples ofsubjects include, without limitation, humans, cows, dogs, cats, goats,sheep, pigs, and rabbits. In some embodiments, the subject is a human.

The term “prodrug” refers to a compound that is made more active invivo. Certain compounds disclosed herein may also exist as prodrugs, asdescribed in Hydrolysis in Drug and Prodrug Metabolism: Chemistry,Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M.Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compoundsdescribed herein are structurally modified forms of the compound thatreadily undergo chemical changes under physiological conditions toprovide the compound. Additionally, prodrugs can be converted to thecompound by chemical or biochemical methods in an ex vivo environment.For example, prodrugs can be slowly converted to a compound when placedin a transdermal patch reservoir with a suitable enzyme or chemicalreagent. Prodrugs may be easier to administer than the compound, orparent drug. They may, for instance, be bioavailable by oraladministration whereas the parent drug is not. The prodrug may also haveimproved solubility in pharmaceutical compositions over the parent drug.A wide variety of prodrug derivatives are known in the art, such asthose that rely on hydrolytic cleavage or oxidative activation of theprodrug. An example, without limitation, of a prodrug would be acompound which is administered as an ester (the “prodrug”), but then ismetabolically hydrolyzed to the carboxylic acid, the active entity.Additional examples include peptidyl derivatives of a compound.

The compounds disclosed herein can exist as therapeutically acceptablesalts. The present invention includes compounds listed above in the formof salts, including acid addition salts. Suitable salts include thoseformed with both organic and inorganic acids. Such acid addition saltswill normally be pharmaceutically acceptable. However, salts ofnon-pharmaceutically acceptable salts may be of utility in thepreparation and purification of the compound in question. Basic additionsalts may also be formed and be pharmaceutically acceptable. For a morecomplete discussion of the preparation and selection of salts, refer toPharmaceutical Salts: Properties, Selection, and Use (Stahl, P.Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

The term “therapeutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds disclosed herein which arewater or oil-soluble or dispersible and therapeutically acceptable asdefined herein. The salts can be prepared during the final isolation andpurification of the compounds or separately by reacting the appropriatecompound in the form of the free base with a suitable acid.Representative acid addition salts include acetate, adipate, alginate,L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate),bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate,formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate),lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, phosphonate, picrate, pivalate, propionate,pyroglutamate, succinate, sulfonate, tartrate, L-tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groupsin the compounds disclosed herein can be quaternized with methyl, ethyl,propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl,dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and sterylchlorides, bromides, and iodides; and benzyl and phenethyl bromides.Examples of acids which can be employed to form therapeuticallyacceptable addition salts include inorganic acids such as hydrochloric,hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic,maleic, succinic, and citric. Salts can also be formed by coordinationof the compounds with an alkali metal or alkaline earth ion. Hence, thepresent invention contemplates sodium, potassium, magnesium, and calciumsalts of the compounds disclosed herein, and the like.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

While it may be possible for the compounds disclosed herein to beadministered as the raw chemical, it is also possible to administer themas a pharmaceutical formulation (or composition). Accordingly, providedherein are pharmaceutical formulations which comprise one or more of thecompounds disclosed herein, or one or more pharmaceutically acceptablesalts, esters, prodrugs, amides, or solvates thereof, together with oneor more pharmaceutically acceptable carriers thereof and optionally oneor more other therapeutic ingredients. The carrier(s) are compatiblewith the other ingredients of the formulation and not deleterious to therecipient thereof. The precise formulation selected will be dependentupon the route of administration chosen and other factors. Any of thewell-known techniques, carriers, and excipients may be used as suitableand as understood in the art; e.g., in Remington's PharmaceuticalSciences. The pharmaceutical compositions disclosed herein may bemanufactured in any manner known in the art, e.g., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or compression processes.

The compounds disclosed herein can be administered in various modes,e.g. orally, topically, or by injection.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, transmucosal, transdermal, rectaland topical (including dermal, buccal, sublingual, ocular, andintraocular) administration although the most suitable route may dependupon for example the condition and disorder of the recipient. Theformulations may conveniently be presented in unit dosage form and maybe prepared by any of the methods well known in the art of pharmacy.Typically, these methods include the step of bringing into associationcompounds disclosed herein or a pharmaceutically acceptable salt, ester,amide, prodrug or solvate thereof (“active ingredient”) with the carrierwhich constitutes one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the compounds disclosed herein suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient mayalso be presented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,capsules (e.g., push-fit capsules made of gelatin, as well as soft,sealed capsules made of gelatin and a plasticizer, such as glycerol orsorbitol) and the like. Tablets may be made by compression or molding,optionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine the activeingredient e.g., in a free-flowing form such as a powder or granules,optionally mixed with binders, inert diluents, or lubricating, surfaceactive or dispersing agents. Molded tablets may be made by molding in asuitable machine a mixture of the powdered compound moistened with aninert liquid diluent. The tablets may optionally be coated or scored andmay be formulated so as to provide slow or controlled release of theactive ingredient therein. All formulations for oral administrationshould be in dosages suitable for such administration. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. Dragee cores areprovided with suitable coatings. For this purpose, concentrated sugarsolutions may be used, which may optionally contain gum arabic, talc,polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/ortitanium dioxide, lacquer solutions, and suitable organic solvents orsolvent mixtures. Dyestuffs or pigments may be added to the tablets ordragee coatings for identification or to characterize differentcombinations of active compound doses.

Examples of fillers or diluents for use in oral pharmaceuticalcompositions such as capsules and tablets include, without limitation,lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressiblesugar, microcrystalline cellulose (MCC), powdered cellulose, cornstarch,pregelatinized starch, dextrates, dextran, dextrin, dextrose,maltodextrin, calcium carbonate, dibasic calcium phosphate, tribasiccalcium phosphate, calcium sulfate, magnesium carbonate, magnesiumoxide, poloxamers such as polyethylene oxide, and hydroxypropyl methylcellulose. Fillers may have complexed solvent molecules, such as in thecase where the lactose used is lactose monohydrate. Fillers may also beproprietary, such in the case of the filler PROSOLV® (available from JRSPharma). PROSOLV® is a proprietary, optionally high-density, silicifiedmicrocrystalline cellulose composed of 98% microcrystalline celluloseand 2% colloidal silicon dioxide. Silicification of the microcrystallinecellulose is achieved by a patented process, resulting in an intimateassociation between the colloidal silicon dioxide and microcrystallinecellulose. PROSOLV® comes in different grades based on particle size,and is a white or almost white, fine or granular powder, practicallyinsoluble in water, acetone, ethanol, toluene and dilute acids and in a50 g/L solution of sodium hydroxide.

Examples of disintegrants for use in oral pharmaceutical compositionssuch as capsules and tablets include, without limitation, sodium starchglycolate, sodium carboxymethyl cellulose, calcium carboxymethylcellulose, croscarmellose sodium, povidone, crospovidone(polyvinylpolypyrrolidone), methyl cellulose, microcrystallinecellulose, powdered cellulose, low-substituted hydroxy propyl cellulose,starch, pregelatinized starch, and sodium alginate.

Additionally, glidants and lubricants may be used in oral pharmaceuticalcompositions to ensure an even blend of excipients upon mixing. Examplesof lubricants include, without limitation, calcium stearate, glycerylmonostearate, glyceryl palmitostearate, hydrogenated vegetable oil,light mineral oil, magnesium stearate, mineral oil, polyethylene glycol,sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearicacid, talc, and zinc stearate. Examples of glidants include, withoutlimitation, silicon dioxide (SiO₂), talc cornstarch, and poloxamers.Poloxamers (or LUTROL®, available from the BASF Corporation) are A-B-Ablock copolymers in which the A segment is a hydrophilic polyethyleneglycol homopolymer and the B segment is hydrophobic polypropylene glycolhomopolymer.

Examples of tablet binders include, without limitation, acacia, alginicacid, carbomer, carboxymethyl cellulose sodium, dextrin, ethylcellulose,gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, copolyvidone,methyl cellulose, liquid glucose, maltodextrin, polymethacrylates,povidone, pregelatinized starch, sodium alginate, starch, sucrose,tragacanth, and zein.

The compounds disclosed herein may be formulated for parenteraladministration by injection, e.g., by bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The pharmaceutical compositions may take forms assuspensions, solutions or emulsions in oily or aqueous vehicles, and maycontain formulatory agents such as suspending, stabilizing and/ordispersing agents. The pharmaceutical compositions may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in powder form or in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example, saline or sterile pyrogen-free water,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

In addition to the pharmaceutical compositions described above, thecompounds may also be formulated as a depot preparation. Such longacting formulations may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

For buccal or sublingual administration, the pharmaceutical compositionsmay take the form of tablets, lozenges, pastilles, or gels formulated inconventional manner. Such compositions may comprise the activeingredient in a flavored basis such as sucrose and acacia or tragacanth.

The compounds disclosed herein may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter, polyethyleneglycol, or other glycerides.

In some embodiments, compounds disclosed herein may be administeredtopically, that is by non-systemic administration. This includes theapplication of a compound disclosed herein externally to the epidermisor the buccal cavity and the instillation of such a compound into theear, eye and nose, such that the compound does not significantly enterthe blood stream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Pharmaceutical compositions suitable for topical administration includeliquid or semi-liquid preparations suitable for penetration through theskin to the site of inflammation such as gels, liniments, lotions,creams, ointments or pastes, and drops suitable for administration tothe eye, ear or nose. The active ingredient for topical administrationmay comprise, for example, from 0.001% to 10% w/w (by weight) of theformulation. In certain embodiments, the active ingredient may compriseas much as 10% w/w. In other embodiments, it may comprise less than 5%w/w. In certain embodiments, the active ingredient may comprise from 2%w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/wof the formulation.

Topical ophthalmic, otic, and nasal formulations of the presentinvention may comprise excipients in addition to the active ingredient.Excipients commonly used in such formulations include, but are notlimited to, tonicity agents, preservatives, chelating agents, bufferingagents, and surfactants. Other excipients comprise solubilizing agents,stabilizing agents, comfort-enhancing agents, polymers, emollients,pH-adjusting agents and/or lubricants. Any of a variety of excipientsmay be used in formulations of the present invention including water,mixtures of water and water-miscible solvents, such as C1-C7-alkanols,vegetable oils or mineral oils comprising from 0.5 to 5% non-toxicwater-soluble polymers, natural products, such as alginates, pectins,tragacanth, karaya gum, guar gum, xanthan gum, carrageenin, agar andacacia, starch derivatives, such as starch acetate and hydroxypropylstarch, and also other synthetic products such as polyvinyl alcohol,polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide,preferably cross-linked polyacrylic acid and mixtures of those products.The concentration of the excipient is, typically, from 1 to 100,000times the concentration of the active ingredient. In preferredembodiments, the excipients to be included in the formulations aretypically selected on the basis of their inertness towards the activeingredient component of the formulations.

Relative to ophthalmic, otic, and nasal formulations, suitabletonicity-adjusting agents include, but are not limited to, mannitol,sodium chloride, glycerin, sorbitol and the like. Suitable bufferingagents include, but are not limited to, phosphates, borates, acetatesand the like. Suitable surfactants include, but are not limited to,ionic and nonionic surfactants (though nonionic surfactants arepreferred), RLM 100, POE 20 cetylstearyl ethers such as PROCOL® CS20 andpoloxamers such as PLURONIC® F68.

The pharmaceutical compositions set forth herein may comprise one ormore preservatives. Examples of such preservatives includep-hydroxybenzoic acid ester, sodium perborate, sodium chlorite, alcoholssuch as chlorobutanol, benzyl alcohol or phenyl ethanol, guanidinederivatives such as polyhexamethylene biguanide, sodium perborate,polyquaternium-1, amino alcohols such as AMP-95, or sorbic acid. Incertain embodiments, the formulation may be self-preserved so that nopreservation agent is required.

For ophthalmic, otic, or nasal administration, the formulation may be asolution, a suspension, or a gel. In some embodiments, thepharmaceutical compositions are for topical application to the eye,nose, or ear in aqueous solution in the form of drops. The term“aqueous” typically denotes an aqueous formulation wherein theformulation is >50%, more preferably >75% and in particular >90% byweight water. These drops may be delivered from a single dose ampoulewhich may preferably be sterile and thus render bacteriostaticcomponents of the formulation unnecessary. Alternatively, the drops maybe delivered from a multi-dose bottle which may preferably comprise adevice which extracts any preservative from the formulation as it isdelivered, such devices being known in the art.

Compositions of the present invention that are adapted for topicaladministration to the eye may be isotonic, or slightly hypotonic inorder to combat any hypertonicity of tears caused by evaporation and/ordisease. This may require a tonicity agent to bring the osmolality ofthe formulation to a level at or near 210-320 milliosmoles per kilogram(mOsm/kg). The formulations of the present invention generally have anosmolality in the range of 220-320 mOsm/kg, and preferably have anosmolality in the range of 235-300 mOsm/kg. The ophthalmic formulationswill generally be formulated as sterile aqueous solutions.

In certain ophthalmic embodiments, the compositions of the presentinvention are formulated with one or more tear substitutes. A variety oftear substitutes are known in the art and include, but are not limitedto: monomeric polyols, such as, glycerol, propylene glycol, and ethyleneglycol; polymeric polyols such as polyethylene glycol; cellulose esterssuch hydroxypropylmethyl cellulose, carboxy methylcellulose sodium andhydroxy propylcellulose; dextrans such as dextran 70; vinyl polymers,such as polyvinyl alcohol; and carbomers, such as carbomer 934P,carbomer 941, carbomer 940 and carbomer 974P. Certain formulations ofthe present invention may be used with contact lenses or otherophthalmic products.

In some embodiments, pharmaceutical compositions are prepared using abuffering system that maintains the formulation at a pH of about 4.5 toa pH of about 8, for example, a pH in a range from about 7 to about 8.

In particular embodiments, a pharmaceutical composition of the presentinvention is administered once a day. However, the compositions may alsobe formulated for administration at any frequency of administration,including once a week, once every 5 days, once every 3 days, once every2 days, twice a day, three times a day, four times a day, five times aday, six times a day, eight times a day, every hour, or any greaterfrequency. Such dosing frequency is also maintained for a varyingduration of time depending on the therapeutic regimen. The duration of aparticular therapeutic regimen may vary from one-time dosing to aregimen that extends for months or years. The formulations may beadministered at varying dosages, but typical dosages are one to twodrops at each administration, or a comparable amount of a gel or otherformulation. One of ordinary skill in the art would be familiar withdetermining a therapeutic regimen for a specific indication.

Gels for topical or transdermal administration may comprise, generally,a mixture of volatile solvents, nonvolatile solvents, and water. Incertain embodiments, the volatile solvent component of the bufferedsolvent system may include lower (C1-C6) alkyl alcohols, lower alkylglycols and lower glycol polymers. In further embodiments, the volatilesolvent is ethanol. The volatile solvent component is thought to act asa penetration enhancer, while also producing a cooling effect on theskin as it evaporates. The nonvolatile solvent portion of the bufferedsolvent system is selected from lower alkylene glycols and lower glycolpolymers. In certain embodiments, propylene glycol is used. Thenonvolatile solvent slows the evaporation of the volatile solvent andreduces the vapor pressure of the buffered solvent system. The amount ofthis nonvolatile solvent component, as with the volatile solvent, isdetermined by the pharmaceutical compound or drug being used. When toolittle of the nonvolatile solvent is in the system, the pharmaceuticalcompound may crystallize due to evaporation of volatile solvent, whilean excess may result in a lack of bioavailability due to poor release ofdrug from solvent mixture. The buffer component of the buffered solventsystem may be selected from any buffer commonly used in the art; incertain embodiments, water is used. A common ratio of ingredients isabout 20% of the nonvolatile solvent, about 40% of the volatile solvent,and about 40% water. There are several optional ingredients which can beadded to the topical composition. These include, but are not limited to,chelators and gelling agents. Appropriate gelling agents can include,but are not limited to, semisynthetic cellulose derivatives (such ashydroxypropylmethylcellulose) and synthetic polymers, galactomannanpolymers (such as guar and derivatives thereof) and cosmetic agents.

Lotions include those suitable for application to the skin or eye. Aneye lotion may comprise a sterile aqueous solution optionally containinga bactericide and may be prepared by methods similar to those for thepreparation of drops. Lotions or liniments for application to the skinmay also include an agent to hasten drying and to cool the skin, such asan alcohol or acetone, and/or a moisturizer such as glycerol or an oilsuch as castor oil or arachis oil.

Creams, ointments or pastes are semi-solid formulations of the activeingredient for external application. They may be made by mixing theactive ingredient in finely-divided or powdered form, alone or insolution or suspension in an aqueous or non-aqueous fluid, with the aidof suitable machinery, with a greasy or non-greasy base. The base maycomprise hydrocarbons such as hard, soft or liquid paraffin, glycerol,beeswax, a metallic soap; a mucilage; an oil of natural origin such asalmond, corn, arachis, castor or olive oil; wool fat or its derivativesor a fatty acid such as stearic or oleic acid together with an alcoholsuch as propylene glycol or a macrogel. The formulation may incorporateany suitable surface active agent such as an anionic, cationic ornon-ionic surfactant such as a sorbitan ester or a polyoxyethylenederivative thereof. Suspending agents such as natural gums, cellulosederivatives or inorganic materials such as silicaceous silicas, andother ingredients such as lanolin, may also be included.

Drops may comprise sterile aqueous or oily solutions or suspensions andmay be prepared by dissolving the active ingredient in a suitableaqueous solution of a bactericidal and/or fungicidal agent and/or anyother suitable preservative, and, in certain embodiments, including asurface active agent. The resulting solution may then be clarified byfiltration, transferred to a suitable container which is then sealed andsterilized by autoclaving or maintaining at 98-100° C. for half an hour.Alternatively, the solution may be sterilized by filtration andtransferred to the container by an aseptic technique. Examples ofbactericidal and fungicidal agents suitable for inclusion in the dropsare phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride(0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for thepreparation of an oily solution include glycerol, diluted alcohol andpropylene glycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavored basis such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a basis such asgelatin and glycerin or sucrose and acacia.

For administration by inhalation, compounds may be convenientlydelivered from an insufflator, nebulizer pressurized packs or otherconvenient means of delivering an aerosol spray. Pressurized packs maycomprise a suitable propellant such as dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Alternatively, for administration by inhalation or insufflation, thecompounds according to the invention may take the form of a dry powdercomposition, for example a powder mix of the compound and a suitablepowder base such as lactose or starch. The powder composition may bepresented in unit dosage form, in for example, capsules, cartridges,gelatin or blister packs from which the powder may be administered withthe aid of an inhalator or insufflator.

Preferred unit dosage formulations are those containing an effectivedose or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the pharmaceutical compositions described above mayinclude other agents conventional in the art having regard to the typeof formulation in question, for example those suitable for oraladministration may include flavoring agents.

A therapeutically effective amount of a compound described herein (e.g.,of Formula I or Formula II or Formula III) can be administered to asubject to treat disease. A therapeutically effective amount is anamount sufficient to produce the intended effect under the conditions ofadministration. For example, an amount that is sufficient to improveglucose uptake, improve glycemic control and/or to improve liverfunction can be administered. The appropriate dosages can be determinedby a clinician of ordinary skill using methods known in the art, whichtake into consideration the individual's age, sensitivity to drugs,tolerance to drugs, severity of disease and overall well-being, as wellas other factors. Suitable dosages can be from about 0.1-about 500.0mg/kg body weight per treatment.

The compounds disclosed herein can be administered by any appropriatemode, for example orally, parenterally (including subcutaneous,intradermal, intramuscular, intravenous, intraarticular, andintramedullary), intraperitoneally, transmucosally, transdermally,rectally a topically (including dermal, buccal, sublingual, ocular, andintraocular). Administration can be of systemic or topical activity asindicated.

In certain instances, it may be appropriate to administer at least oneof the compounds described herein (or a pharmaceutically acceptablesalt, ester, or prodrug thereof) in combination with another therapeuticagent. When a compound of Formula I or II or III is administered withanother therapeutic agent, the compound can be administered before,substantially at the same time as or after the other therapeutic agent.In general, the compound and the other therapeutic agent areadministered to provide substantial overlap of their respectivetherapeutic effects. By way of example only, in a treatment for diabetesinvolving administration of one of the compounds described herein,increased therapeutic benefit may result by also providing the patientwith another therapeutic agent for diabetes. In any case, regardless ofthe disease, disorder or condition being treated, the overall benefitexperienced by the patient may simply be additive of the two therapeuticagents or the patient may experience a synergistic benefit.

Non-limiting examples of possible combination therapies include use ofcertain compounds disclosed herein with biologics of E4orf1.

Thus, in another aspect, certain embodiments provide methods fortreating disease or disorders comprising administering to a subject atherapeutically effective amount of a compound of Formula I or II orIII, optionally with another therapeutic agent. The disease or disorderto be treated in accordance with the invention can be hyperglycemia,insulin resistance, prediabetes, diabetes type 1, diabetes type 2,hepatic steatosis, NAFLD, non-alcoholic steato-hepatitis (NASH), andliver dysfunction (e.g., liver dysfunction characterized by fatty liverand/or insulin resistance), metabolic syndrome, polycystic ovarysyndrome (PCOS). Advantageously, treatment of these diseases with acompound of Formula I or II or III does not increase adiposity in thesubject.

In some embodiments, the invention is a method of treating diabetes(type 1 and/or type 2) comprising administering to a subject in needthereof a therapeutically effective amount of a compound of Formula I orII or III. Advantageously, the method can be used to treat diabeteswithout substantially increasing adipogenesis in the subject.

In some embodiments, the invention is a method of treatinghyperglycemia, insulin resistance associated with PCOS, metabolicsyndrome, Alzheimer's disease, and/or prediabetes, comprisingadministering to an subject in need thereof a therapeutically effectiveamount of a compound of Formula I or II or III. Advantageously, themethod can be used to treat hyperglycemia, insulin resistance associatedwith PCOS, metabolic syndrome, Alzheimer's disease and/or prediabeteswithout substantially increasing adipogenesis in the subject.

In some embodiments, the invention is a method of treating liverdysfunction (e.g., liver dysfunction characterized by fatty liver and/orinsulin resistance) comprising administering to a subject in needthereof a therapeutically effective amount of a compound of Formula I orII or III. Advantageously, the method can be used to treat liverdysfunction (e.g., liver dysfunction characterized by fatty liver and/orinsulin resistance) without substantially increasing adipogenesis in thesubject.

In some embodiments, the invention is a method of treating hepaticsteatosis comprising administering to a subject in need thereof atherapeutically effective amount of a compound of Formula I or II orIII. Advantageously, the method can be used to treat hepatic steatosiswithout substantially increasing adipogenesis in the subject.

In some embodiments, the invention is a method of treating NAFLDcomprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of Formula I or II or III.Advantageously, the method can be used to treat NAFLD withoutsubstantially increasing adipogenesis in the subject.

In some embodiments, the invention is a method of treating NASHcomprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of Formula I or II or III.Advantageously, the method can be used to treat NASH withoutsubstantially increasing adipogenesis in the subject.

It is understood that modifications which do not substantially affectthe activity of the various embodiments of this invention are alsoincluded within the definition of the invention provided herein.Accordingly, the following examples are intended to illustrate but notlimit the present invention.

EXAMPLES Materials and Methods

All reagents were purchased from commercial sources and used withouttreatment, unless otherwise indicated. The products were purified bycolumn chromatography over silica gel. ¹H NMR and ¹³C NMR spectra wererecorded at 25° C. at 400 MHz and 100 MHz respectively, with TMS asinternal standard. Abbreviations for signal coupling are as follows: s,singlet; d, doublet; q, quartet; m, multiplet. Chemical shifts (6) wererecorded in ppm and coupling constants (J) in hertz (Hz). Columnchromatography was performed using SiO₂ (60 A°, 230-400 mesh) from SigmaAldrich. All reagents were obtained from commercial sources. Indesigning compounds of Formulas I, II and III, the protein sequence wasdetermined in-silico, and the active site of E4orf1 protein of Ad36virus was modeled with ICM software (Halgren, T. A. Merck molecularforce field 0.1. Basis, form, scope, parameterization, and performanceof MMFF94. Journal of Computational Chemistry 1996, 17, 490-519; Totrov,M.; Abagyan, R. Flexible protein-ligand docking by global energyoptimization in internal coordinates. Proteins 1997, 215-220) and theactive site of the protein was generated. After generating active siteof protein in-silico, a small library of chemical compounds wasscreened. After identifying these compounds in-silico, exemplarymolecules 1-11 were synthesized based on transformations disclosedherein. A common motif in the compounds disclosed herein is thealpha-aminonitrile pharmacophore. Compounds 1-11 below were synthesized.

Example 12-(4-hydroxyphenyl)-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)acetonitrile

4-hydroxyl-benzaldehyde A (0.1 mmol, 0.122 g) and 4-aminophenylboronicacid pinacol ester B (1.0 mmol, 0.219 g) were dissolved in 0.5 mL THF(tetrahydrofuran) and 2 mL H₂O, and then InCl₃ (indium chloride) (0.1mmol, 0.022 g) and TMSCN (trimethylsilyl cyanide) (0.12 mmol, 0.12 g)were added. After overnight, ethyl acetate was added, washed with waterthree times, the organic layer was dried over anhydrous sodium sulfate,and evaporated to give an off-white solid. Further purification was doneby silica gel column chromatography using hexane:ethyl acetate of ratio4:1 to give 0.19 g of product 1. ¹H NMR (d-DMSO) δ: 9.70 (1H, s), 7.48(21-1, d), 7.37 (2H, d), 6.84 (4H, m), 6.93 (1H, d), 5.89 (1H, d), 1.26(12H, s).

Example 2 Potassium(4-((cyano(4-hydroxyphenyl)methyl)amino)phenyl)trifluoroborate

Example 1 (0.286 mmol, 0.1 g) was added to 10 mL methanol, and then 3 MKHF₂ (1.29 mmol, 0.11 g) was added. The mixture was stirred for 30 minand methanol was evaporated. The crude product was dissolved in acetoneand filtered, and the filtrate was evaporated to get white solid whichwas further recrystallized in acetone and diethyl ether to yield 0.04 gof pure product 2. ¹H NMR (d-DMSO) δ: 7.37 (2H, d, J=8.6 Hz), 7.12 (2H,d, J=8.0 Hz), 6.81 (2H, d, J=8.0 Hz), 6.61 (2H, d, J=8.0 Hz), 5.94 (2H,d, J=8.0 Hz), 5.68 (2H, d, J=10.0 Hz).

Example 32-(pyridin-3-yl)-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)acetonitrile

3-pyridine carboxaldehyde (0.1 mmol, 0.122 g), 4-aminophenylboronic acidpinacol ester (1.0 mmol, 0.219 g) was dissolved in 2 mL H₂O, and thenInCl₃ (0.1 mmol, 0.022 g) and TMSCN (0.12 mmol, 0.12 g) were added.After overnight, ethyl acetate was added, washed with water three times,and the organic layer was dried. The crude product was purified bycolumn chromatography using hexane:ethyl acetate of 2:1 ratio to obtain0.13 g of product 3. ¹H NMR (CDCl₃) δ: 8.76 (1H, s), 8.63 (1H, d, J=4Hz), 7.89 (1H, d, J=4 Hz), 7.72 (2H, d, J=12 Hz), 7.37 (1H, q, J=4 Hz),6.75 (2H, d, J=8 Hz), 5.53 (1H, d, J=8 Hz), 4.78 (1H, d, J=8 Hz).

Example 42-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-2-(2,6,6-trimethylcyclohex-1-en-1-yl)acetonitrile

β-cyclocitral (0.1 mmol, 0.152 g, 0.17 ml), 4-aminophenylboronic acidpinacol ester (1.0 mmol, 0.219 g) was dissolved in 2 mL H₂O, and thenInCl₃ (0.1 mmol, 0.022 g) and TMSCN (0.12 mmol, 0.12 g) were added.After overnight, the reaction mixture was extracted in ethyl acetate,washed with water and the organic layer was dried. The obtained solidwas purified by silica gel column to give 0.13 g of final product 4. ¹HNMR (CDCl₃) δ: 8.63 (1H, s), 6.72, (2H, d, J=8 Hz), 6.62 (2H, d, J=8Hz), 5.19 (1H, d, J=8 Hz), 4.69 (1H, d, J=8 Hz), 2.00 (2H, m), 1.89 (3H,s), 1.46-1.41 (4, m).

Example 5 2-((4-hydroxyphenyl)amino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile

4-formyl phenylboronic acid pinacol ester (0.1 mmol, 0.232 g), 4-aminophenol (1.0 mmol, 0.109 g) was dissolved in 2 mL H₂O, and then InCl₃(0.1 mmol, 0.022 g) and TMSCN (0.12 mmol, 0.12 g) were added. Afterovernight, the reaction mixture was extracted in ethyl acetate, washedwith water and the organic layer was dried. The obtained solid waspurified by silica gel column to yield 0.21 g of final product 5. ¹H NMR(CDCl₃) δ: 8.74 (1H, s), 7.75 (2H, d. J=8 Hz), 7.59 (2H, d, J=8 Hz),6.69 (2H, d, J=8 Hz), 6.61 (2H, d, J=8 Hz), 6.14 (1H, d, J=8 Hz) 5.88(1H, d, J=8 Hz).

Example 62-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)acetonitrile

4-formyl phenylboronic acid pinacol ester (0.1 mmol, 0.232 g),4-aminophenylboronic acid pinacol ester (1.0 mmol, 0.109 g) wasdissolved in 0.5 THF and 2 mL H₂O, and then InCl₃ (0.1 mmol, 0.022 g)and TMSCN (0.12 mmol, 0.12 g) were added. After overnight, the reactionmixture was extracted in ethyl acetate, washed with water and theorganic layer was dried. The obtained solid was purified by silica gelcolumn to obtain 0.23 g of final product 6. ¹H NMR (CDCl₃) δ: 7.89 (2H,d, J=8 Hz), 7.73 (2H, d, J=8 Hz), 7.29 (2H, d, J=8 Hz), 6.75 (2H, d, J=8Hz), 5.49 (1H, d, J=8 Hz), 4.19 (1H, d, J=12 Hz), 1.36 (6H, s), 1.33(6H, s).

Example 72-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-2-(3,4,5-trimethoxyphenyl)acetonitrile

3,4,5-trimethoxybenzaldehyde (0.1 mmol, 0.196 g), 4-aminophenylboronicacid pinacol ester (1.0 mmol, 0.109 g) was dissolved in 0.5 mL THF and 2mL H₂O, and then InCl₃ (0.1 mmol, 0.022 g) and TMSCN (0.12 mmol, 0.12 g)were added. After overnight, the reaction mixture was extracted in ethylacetate, washed with water, organic layer was dried. The solid waspurified by column chromatography using hexane:ethyl acetate of 3:1ratio to yield 0.23 g of pure compound 7. ¹H NMR (CDCl₃) δ: 7.74 (2H, d,J=8 Hz), 6.79 (2H, s), 6.77 (2H, d, J=8 Hz), 5.41 (1H, d, J=8 Hz), 4.24(1H, d, J=8 Hz), 3.89 (6H, s), 3.87 (3H, s).

Example 8 Potassium(4-((cyano(3,4,5-trimethoxyphenyl)methyl)amino)phenyl) trifluoroborate

Example 7 (0.235 mmol, 0.1 g) was added to 10 mL methanol, and then 3 MKHF₂ (1.06 mmol, 0.082 g) was added. After the mixture was stirred for30 min, methanol was evaporated. The crude product was dissolved inacetone and filtered, and the filtrate was evaporated to get white solidwhich was further recrystallized in acetone and diethyl ether to yield0.06 g of pure product 8. ¹H NMR (CDCl₃) δ: 7.14 (2H, d, J=8 Hz), 6.95(211, s), 6.63 (2H, d, J=4 Hz), 6.06 (2H, d, J=8 Hz), 5.73 (2H, d, J=8Hz), 3.8 (6H, s), 3.67 (3H, s).

Example 9 Potassium(4-((cyano(pyridin-3-yl)methyl)amino)phenyl)trifluoroborate

Example 3 (0.235 mmol, 0.1 g) was added to 10 mL methanol, and then 3 MKHF₂ (1.06 mmol, 0.082 g) was added. After the mixture was stirred for30 min, methanol was evaporated. The crude product was dissolved inacetone and filtered, and the filtrate was evaporated to get white solidwhich was further recrystallized in acetone and diethyl ether to give0.03 g of pure product 9. ¹H NMR (d-DMSO) δ: 8.76 (1H, s), 8.62 (1H, s),7.99 (1H, s), 7.51, (2H, d, J=8 Hz), 7.14 (1H, d, J=8 Hz), 6.82 (1H, d,J=8 Hz), 6.63 (1H, d, J=8 Hz), 6.21 (1H, d, J=8 Hz), 6.00 (1H, d, J=8Hz).

Example 10 Potassium(4-(cyano((4-hydroxyphenyl)amino)methyl)phenyl)trifluoroborate

Example 5 (0.286 mmol, 0.11 g) was added to 10 mL methanol, and then 3 MKHF₂ (1.29 mmol, 0.11 g) was added. After the mixture was stirred for 30min, methanol was evaporated. The crude product was dissolved in acetoneand filtered, and the filtrate was evaporated to obtain a white solidwhich was further recrystallized in acetone and diethyl ether to yield0.07 g of final product 10. ¹H NMR (d-DMSO) δ: 8.67 (1H, s), 7.38 (2H,d, J=8 Hz), 7.29 (2H, d, J=8 Hz), 6.70 (2H, d, J=8 Hz), 6.60 (2H, d, J=8Hz).

Example 11 Potassium (4-(cyano((4-(potassiumtrifluoroborate-phenyl)amino)methyl)phenyl)trifluoroborate

Example 6 (0.217 mmol, 0.1 g) was added to 10 mL methanol, and then 3MKHF₂ (1.95 mmol, 0.153 g) was added. After the mixture was stirred for30 min, methanol was evaporated. The crude product was dissolved inacetone and filtered, and the filtrate was evaporated to give a whitesolid which was further recrystallized in acetone and diethyl ether toyield 0.08 g of final product 11. ¹H NMR (D₂O) δ: 7.44 (2H, d, J=8 Hz),7.36 (2H, d, J=8 Hz), 7.28 (2H, d, J=8 Hz), 6.77 (2H, d, J=8 Hz), 5.55(1H, s).

Example 12 Biological Activity

Glucose uptake by 3T3-L1 cells exposed to compounds 1-11 was determinedat 5 μM concentration. Cells were exposed to compounds 1-11 for 24 hoursand exposure to DMSO was used as the control group. 2-Deoxy glucose(2-DG) uptake was determined using the analog compounds without serumstarving the cells prior to determining glucose uptake. Glucose uptakein 3T3-L1 pre-adipocytes was determined by exposing cells to compounds1-11 for 24 hours without serum starvation. Percent increase in glucoseuptake in basal conditions due to the exposure to a compound is shown inthe Table below. P values presented in the Table indicate statisticalsignificance (p<0.05). P values are not presented for compounds that didnot increase glucose uptake significantly.

Glucose uptake assays of compounds p value Percent increase in glucose pvalue T-test with uptake in comparison to Students Bonferroni ExampleDMSO treated Control T-test Adjustment 1 24% 0.001 0.02 2 No increase 3 9% 4 33% 0.04 5 73% 0.0000001 0.000003 6 17% 0.003 7 41% 0.00004 0.00068 43% 0.0005 0.01 9 54% 0.00003 0.0006 10 31% 0.001 0.02 11 53% 0.0020.04

Throughout this application various publications have been referenced.The disclosures of these publications in their entireties are herebyincorporated by reference in this application in order to more fullydescribe the state of the art to which this invention pertains.

Although the invention has been described with reference to thedisclosed embodiments, those skilled in the art will readily appreciatethat the specific examples and studies detailed above are onlyillustrative of the invention. It should be understood that variousmodifications can be made without departing from the spirit of theinvention. Accordingly, the invention is limited only by the followingclaims.

What is claimed is:
 1. A compound comprising the structure of generalFormula I, pharmaceutically acceptable salts thereof, and/or solvatesthereof:

wherein Ar₁ is selected from the group consisting of 6-membered aryl and6-membered heteroaryl, each of which is optionally substituted, Ar₂ isselected from the group consisting of 6-membered aryl and 6-memberedheteroaryl, each of which is optionally substituted.
 2. A compoundcomprising the structure of general Formula II, pharmaceuticallyacceptable salts thereof, and/or solvates thereof:

wherein Z¹, Z², Z³, Z⁴, Z⁵ and Z⁶ are each independently selected fromthe group consisting of

null, alkyl, aryl, heteroaryl, alkoxy, hydroxy, thiol, trifluoromethyl,nitrile, isonitrile and halogen, wherein the alkyl, aryl, heteroaryl,alkoxy, hydroxy and thiol may be optionally substituted, with theproviso that no more than one of Z¹, Z² and Z³ is

and no more than one of Z⁴, Z⁵ and Z⁶ is

R¹ and R² are independently selected from the group consisting ofhydroxy, alkoxy, and halo, and R³ is selected from the group consistingof null, hydroxy, alkoxy, and halo, or R¹ and R² taken together with theboron atom to which they are bonded form a cyclic boronate ester and R³is null, wherein when four bonds to boron are present, boron bears aformal negative charge and the structure further comprises a countercation selected from the group consisting of potassium and sodium; andX¹, X², X³, X⁴ and X⁵ are independently selected from the groupconsisting of O, C, S, B(—R⁴) and N, with the proviso that no more thantwo of X¹, X², X³, X⁴ and X⁵ are O, S, B(—R⁴) or N; and each R⁴ isindependently selected from the group consisting of hydrogen, optionallysubstituted hydroxy, optionally substituted alkoxy and optionallysubstituted alkyl.
 3. A compound comprising the structure of generalFormula III, pharmaceutically acceptable salts thereof, and/or solvatesthereof:

wherein Z¹, Z², Z³ and Z⁴ are each independently selected from the groupconsisting of

null, alkyl, aryl, heteroaryl, alkoxy, hydroxy, thiol, trifluoromethyl,nitrile, isonitrile and halogen, wherein the alkyl, aryl, heteroaryl,alkoxy, hydroxy and thiol may be optionally substituted, with theproviso that no more than one of Z¹, Z² and Z³ is

R¹ and R² are independently selected from the group consisting ofhydroxy, alkoxy, and halo, and R³ is selected from the group consistingof null, hydroxy, alkoxy, and halo, or R¹ and R² taken together with theboron atom to which they are bonded form a cyclic boronate ester and R³is null, wherein when four bonds to boron are present, boron bears aformal negative charge and the structure further comprises a countercation selected from the group consisting of potassium and sodium; andX¹, X², X³, X⁴ and X⁵ are independently selected from the groupconsisting of O, C, S, B(—R⁴) and N, with the proviso that no more thantwo of X¹, X², X³, X⁴ and X⁵ are O, S, B(—R⁴) or N; and each R⁴ isindependently selected from the group consisting of hydrogen, optionallysubstituted hydroxy, optionally substituted alkoxy and optionallysubstituted alkyl.
 4. The compound of claim 1 that is selected from thegroup consisting of:

and pharmaceutically acceptable salts and/or solvates thereof.
 5. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable vehicle.
 6. A method of treating a diseasecomprising administering to a subject a therapeutically effective amountof a compound of claim
 1. 7. The method of claim 6, wherein the diseaseis selected from the group consisting of hyperglycemia, insulinresistance, metabolic syndrome, polycystic ovary syndrome (PCOS),prediabetes, diabetes type 1, diabetes type 2, hepatic steatosis, NAFLD,non-alcoholic steato-hepatitis (NASH), and liver dysfunction (e.g.,liver dysfunction characterized by fatty liver and/or insulinresistance), and combinations thereof.
 8. A method of treating a diseasecomprising administering to a subject a therapeutically effective amountof a pharmaceutical composition of claim
 5. 9. The method of claim 8,wherein the disease is selected from the group consisting ofhyperglycemia, insulin resistance, metabolic syndrome, polycystic ovarysyndrome (PCOS), prediabetes, diabetes type 1, diabetes type 2, hepaticsteatosis, NAFLD, non-alcoholic steato-hepatitis (NASH), and liverdysfunction (e.g., liver dysfunction characterized by fatty liver and/orinsulin resistance), and combinations thereof.